The pathogenetic mechanisms responsible for the induction of hepatocellular injury and viral clearance in hepatitis B virus (HBV) infection remain to be clarified. Our studies in this area have been focussed during the last 2 years on the peripheral blood helper T cell reactivity to HBV envelope and nucleocapsid antigens in order to compare the features of these responses in patients who successfully clear the virus with those who do not. Results of such studies indicate 1) that a strong magnitude peripheral blood helper T cell response to HBV nucleocapsid antigens is temporally associated with viral clearance and focussed on an immunodominant epitope within the hepatitis B core antigen (HBcAg); 2) that the peripheral blood helper T cell response to HBV envelope antigens is weak and inconstant during HBVjinfection, but is readily detectable in high responder vaccine recipients who are particularly responsive to multiple determinants within the preS 1 region of the envelope proteins. Although our results suggest that the helper T cell response to HBcAg plays an important role in HBV clearance, definitive demonstration requires parallel analysis of the helper, suppressor and cytotoxic T cell responses to HBV antigens in the peripheral blood and intrahepatic compartments, since the peripheral blood may only partially reflect the immune events taking place at the site of infection and injury. Therefore, our proposal is primarily aimed at investigating the relative importance of the different HBV antigens as sensitizing molecules for intrahepatic T cells from patients at different stages of HBV infection and the relative representation of the different T cell functions (helper, suppressor and cytotoxic) among T cell populations of different HBV antigen specificity. The study will be primarily carried out at the clonal level assessing phenotype, fine specificity, HLA-restriction, function and frequency of HBV-specific T cells. When the magnitude and quality of the peripheral blood and intrahepatic T cell responses to HBV encoded antigens have been compared, it should be possible to determine the extent to which the HBV antigen-specific T cell response is pathogenetically related to virus induced injury and to viral clearance in this disease.